The present invention relates to substituted aminomethyl-phenyl-cyclohexane derivatives and processes for their preparation, their use for the preparation of medicaments and medicaments comprising these compounds.
Treatment of chronic and non-chronic states of pain is of great importance in medicine. There is a worldwide need for pain treatments with a good action for target-orientated treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood successful and satisfactory pain treatment for the patient. This manifests itself in the large number of scientific works which have been published in the field of applied analgesia and basic research in nociception in recent years.
Conventional opioids, such as morphine, have a good action in the treatment of severe to very severe pain. However, their use is limited by their known side effects, e.g. respiratory depression, vomiting, sedation, constipation, addiction, dependency and development of tolerance. They can therefore be administered over a relatively long period of time or in relatively high dosages only if particular safety precautions are taken, such as specific prescription instructions (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). They furthermore show a lower activity with some states of pain, in particular neuropathic pain.
Tramadol hydrochloridexe2x80x94(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloridexe2x80x94is another known therapeutic for treatment of severe pain. It occupies a special position among analgesics having an action on the central nervous system, inasmuch as this active compound brings about potent inhibition of pain without the side effects known of opioids (J. Pharmacol. Exptl. Ther. 267, 33 (1993)), both the enantiomers of tramadol and the enantiomers of tramadol metabolites participating in the analgesic action (J. Pharmacol. Exp. Ther. 260, 275 (1992)). Needless to say, tramadol is also not without side effects.
There is thus a need to provide substances which have an analgesic action and are suitable for treatment of pain. These substances should furthermore have as few side effects as possible, such as nausea, dependency, respiratory depression or constipation.
This object is achieved by the substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention. The invention therefore provides substituted aminomethyl-phenyl-cyclohexane derivatives of the general formula I and Ia, also in the form of their diastereomers or enantiomers and of their free bases or of a salt formed with a physiologically tolerated acid, in particular the hydrochloride salt. 
wherein
R1 and R1xe2x80x2 independently of one another are
H, C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; F; Cl; Br; I; NR6R6xe2x80x2; NO2; CN; OR6; SR6; OC(O)R6; C(O)OR6; C(O)R6 or C(O)NR6R6, wherein R6 and R6xe2x80x2 are
H; C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by N, S or O; alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
R1 and R1 together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 resulting in a naphthyl system which can be mono- or polysubstituted,
X is
H, F, Cl, Br, I, CF3, OS(O2)C6H4-pCH3, OR7 or OC(O)R7, wherein R7 is
H; C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by N, S or O; alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
if the compound contains no X, according to formula Ia a double bond is formed between C atom A and C atom B or C atom B and C atom C,
R4, R5 independently of one another are
H; C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by N, S or O; alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
R4 and R5 together form a C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR8, wherein R8 is H; or C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
and
R2, R3 independently of one another are
R9 or YR9, wherein Y is C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, branched or unbranched and mono- or polysubstituted or unsubstituted, wherein R9 is
H; F; Cl; Br; I; CN; NO2; C1-C18-alkyl, C2-C18-alkenyl or C2-C18-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; or C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR10, where R10 is
H; or C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
OR11, OC(O)R11, OC(O)OR11, OC(S)R11, C(O)R11, C(O)OR11, C(S)R11, C(S)OR11, SR11, S(O)R11 or S(O2)R11, wherein R11 is
H; C1-C18-alkyl, C2-C18-alkenyl or C2-C18-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR12, where R12 is chosen from
H, C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;
NR13R14, NR13C(O)R14, C(O)NR13R14 or S(O2)NR13R14, wherein R13 and R14 independently of one another are
H; O; C1-C18-alkyl, C2-C18-alkenyl or C2-C18-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR15, where R15 is
H, C1-C10-alkyl, C2-C10-alkenyl or C2-C10 xe2x80x94alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
R13 and R14 together form a C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR16, where R16 is
H; or C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; or
alkylaryl, aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; in particular 
wherein R17, R18, R19 and R20 independently of one another are
R21 or ZR21, whereing Z is C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted, and wherein R21 is
H; F; Cl; Br; I; CN; NO2; C1-C18-alkyl, C2-C18-alkenyl or C2-C18-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR22, where R22 is
xe2x80x83H; or C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
or alkylaryl, aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;
OR23, OC(O)R23, OC(O)OR23, OC(S)R23, C(O)R23, C(O)OR23, C(S)R23, C(S)OR23, SR23, S(O)R23 or S(O2)R23, wherein R23 is
xe2x80x83H; or C1-C18-alkyl, C2-C18-alkenyl or C2-C18-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR24, where R24 is
xe2x80x83H; or C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;
NR25R26, NR25C(O)R26, C(O)NR25R26 or S(O2)NR25R26, wherein R25 and R26 independently of one another are
xe2x80x83H; C1-C18-alkyl, C2-C18-alkenyl or C2-C18-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR27, where R27 is
xe2x80x83H; or C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
xe2x80x83alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
wherein R25 and R26 together form a C3-C7-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR27, where R27 is
xe2x80x83H; or C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted.
In connection with alkyl, alkenyl, alkinyl and cycloalkyl and the xe2x80x9ccorresponding heterocyclic radical,xe2x80x9d the term substituted in the context of this invention is understood as meaning the replacement of a hydrogen radical by F, Cl, Br, I, NH2, SH or OH; and polysubstituted radicals is understood as meaning radicals which are substituted more than once either on different or on the same atom, for example three times on the same C atom, as in the case of CF3, or at different places, as in the case of xe2x80x94CH(OH)xe2x80x94CHxe2x95x90CHxe2x80x94CHCl2.
Furthermore, xe2x80x94C(O)xe2x80x94 denotes 
which also applies to xe2x80x94C(S)xe2x80x94 or xe2x80x94S(O)xe2x80x94 and xe2x80x94S(O2)xe2x80x94.
The term xe2x80x9cC1-C8-alkylxe2x80x9d or xe2x80x9cC1-C10-alkylxe2x80x9d in the context of this invention denotes hydrocarbons having 1 to 8, or 1 to 10 carbon atoms respectively. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butane, sec-butyl, tert-butyl, n-pentane, neopentyl, n-hexane, n-heptane, n-octane, n-nonane or n-decane.
The term xe2x80x9cC1-C18-alkylxe2x80x9d in the context of this invention denotes hydrocarbons having 1 to 18 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butane, sec-butyl, tert-butyl, n-pentane, neopentyl, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tridecane, n-tetradecane, n-pentadecane, n-hexadecane, n-heptadecane or n-octadecane, unsubstituted or mono or polysubstituted.
The term xe2x80x9cC2-C10-alkenylxe2x80x9d or xe2x80x9cC2-C10-alkinylxe2x80x9d or xe2x80x9cC2-C18-alkenylxe2x80x9d or xe2x80x9cC2-C18-alkinylxe2x80x9d in the context of this invention denotes hydrocarbons having 2 to 8 or 2 to 18 carbon atoms respectively. Examples which may be mentioned are propenyl, butenyl, pentenyl, hexenyl, heptenyl or octenyl, unsubstituted or mono or polysubstituted, or propinyl, butinyl, pentinyl, hexinyl, heptinyl or octinyl, unsubstituted or mono or polysubstituted.
The term C3-C7-cycloalkyl in the context of this invention denotes cyclic hydrocarbons having 3 to 7 carbon atoms in the ring. Examples which may be mentioned are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl or cycloheptenyl, saturated or unsaturated and unsubstituted or mono- or polysubstituted. In the context of the invention a xe2x80x9ccorresponding heterocyclic radicalxe2x80x9d is understood as meaning a C3-C7-cycloalkyl in which one C atom in the ring is replaced by S, O or N. Examples which may be mentioned for this are pyrrolidine, pyran, thiolane, piperidine or tetrahydrofuran.
The term xe2x80x9carylxe2x80x9d in the context of this invention denotes phenyls or naphthyls.
The term xe2x80x9calkylarylxe2x80x9d in the context of this invention denotes aryls substituted by at least a C1-C10-alkylene, the terms aryl and alkyl having the same meaning as above. In this group benzaryl may be mentioned in particular.
The term xe2x80x9cheteroarylxe2x80x9d in the context of this invention denotes a 5- or 6-membered aromatic compound which is optionally provided with a fused-on ring system and contain one or two heteroatoms selected from the groups consisting of nitrogen, oxygen and sulfur. Examples which may be mentioned in this group are furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline.
In respect of aryl, alkylaryl or heteroaryl, mono- or polysubstituted in the context of this invention is understood as meaning substitution of the ring system on one or more atoms by F; Cl; Br; I; NH2; SH; OH; CF3; or mono- or polysubstituted or unsubstituted C1-C6-alkyl, C1-C6-alkoxy, C2-C8-alkenyl, C2-C8-alkinyl; or aryl, in particular phenyl.
The phrase xe2x80x9cSalt formed with a physiologically tolerated acidxe2x80x9d in the context of this invention is understood as meaning salts of the particular active compound with inorganic or organic acids which are physiologically toleratedxe2x80x94in particular when used in humans and/or other mammals. Hydrochloride salts are particularly preferred.
Preferably, in formula I or Ia, R2 and R3 have different meanings and/or R3 is H or CH3, preferably H, while R1, R1xe2x80x2, R2, R4, R5 and X are as defined above.
More preferably, in formula I or Ia, R2 is 
wherein R17, R18, R19 and R20, as well as R1, R1xe2x80x2, R3, R4, R5 and X have meanings as defined above.
Preferably R2 is a C1-3-alkyl.
In another preferred embodiment in formula I or Ia, R2 is 
and R19 and R20 are H, while R1, R1xe2x80x2, R3, R4, R5, X and R17 and R18 are as defined above.
In a further preferred embodiment, aminomethyl-phenyl-in formula I or Ia according to the invention, R2 is 
wherein R17 and R18 have a different meaning and/or R18 is R21, wherein R21 is
H, F, Cl, Br, I, CF3 or OR23, where R23 is H, methyl ethyl, propyl, isopropyl, butyl or isobutyl,
while R1, R1xe2x80x2, R3, R4, R5 and X, as well as R17, R19 and R20 have one of the meanings defined above.
More preferably, in formula I or Ia according to the invention, R2 is 
wherein R17 is
R21, wherein R21 is
H, F, Cl, Br, I, CF3, OR23, OC(O)R23, C(O)R23 or C(O)OR23, preferably H, F, Cl, C(O)OR23, wherein R23 is
H; or C1-C6-alkyl, C2-C8-alkenyl or C2-C8-alkinyl, in particular C1-C4-alkyl, branched or unbranched and mono- or polysubstituted or unsubstituted; preferably H, methyl ethyl, propyl, isopropyl, butyl or isobutyl, in particular H, CH3, C2H5 or isobutyl;
or C(O)NR25R26, wherein R25 and R26 independently of one another are
H; 0; or C1-C18-alkyl, in particular C1-C4-alkyl, branched or unbranched, saturated or unsaturated and mono- or polysubstituted or unsubstituted; preferably H, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, in particular C2H5; or
ZR21, where Z is CH2 or C2H4, preferably CH2, wherein R21 is
OR23, OC(O)R23, C(O)R23 or C(O)OR23, preferably OR23, wherein R23 is
H; or C1-C6-alkyl, C2-C8-alkenyl or C2-C8-alkinyl, in particular C1-C4-alkyl, branched or unbranched and mono- or polysubstituted or unsubstituted, preferably H, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, in particular H;
C(O)NR25R26, wherein R25 and R26 independently of one another are chosen from
H, O, C1-C18-alkyl, in particular C1-C4-alkyl, branched or unbranched, saturated or unsaturated and mono- or polysubstituted or unsubstituted, preferably H, methyl ethyl, propyl, isopropyl, butyl or isobutyl;
while R1, R1xe2x80x2, R3, R4, R5 and X and R18, R19 and R20 are as defined above.
In a particularly preferred embodiment in formula I or Ia according to the invention
R1 is
H, F, Cl, Br, I, CF3, SCH3 or OR6, preferably OR6, wherein R6 is
H; or C1-C4-alkyl, branched or unbranched and mono- or polysubstituted or unsubstituted; preferably H or CH3; and/or
R1 is
H, F, Cl, SCH3 or OCH3, preferably H and/or
X is
H, F, Br, I, Cl or OR7, preferably H, F, Cl or OR7, where R7 is H or CH3, preferably H; or
if the compound contains no X, according to formula Ia a double bond is formed between C atom A and C atom B or C atom B and C atom C; and/or
R4 and R5 independently of one another are
C1-C4-alkyl, branched or unbranched and mono- or polysubstituted or unsubstituted, preferably CH3,
while R2 and R3 have one of the above-defined meanings.
The following substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention are particularly preferred:
rac-cis-E-[-4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-trans-E-[4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-trans-Z-[4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-cis-Z-[4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-naphthalene-1-carboxylic acid ethyl ester,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-naphthalene-1-carboxylic acid ethyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-2-fluoro-benzoic acid ethyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid,
E-{3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-phenyl}-methanol,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-[3-(2-dimethylaminomethyl-5-(3-hydroxymethyl-benzylidene)-cyclohexyl)-phenol,
rac-trans-E-3-(5-benzylidene-2-dimethylaminomethyl-cyclohexyl)-phenol,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid tert-butyl ester,
E-3-[6-dimethylaminomethyl-3-(3-hydroxymethyl-benzylidene)-cyclohex-1-enyl]-phenol,
rac-trans-Z-3-(5-benzylidene-2-dimethylaminomethyl-cyclohexyl)-phenol,
Z-3-[2-dimethylaminomethyl-5-(3-hydroxymethyl-benzylidene)-cyclohex-1-enyl]-phenol,
Z-{3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-phenyl}-methanol,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid tert-butyl ester,
rac-trans-E-[3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl)-phenyl)-methanol],
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid ethyl ester,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid ethyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-N,N-diethyl-benzamide,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-N,N-diethyl-benzamide,
E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid isobutyl ester,
Z-3-[6-dimethylaminomethyl-3-(3-hydroxymethyl-benzylidene)-cyclohex-1-enyl]-phenol,
Z-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
E-[4-(4-fluoro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
Z-[4-(4-fluoro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
E-3-[6-dimethylaminomethyl-3-(4-fluoro-benzylidene)-cyclohex-1-enyl]-phenol,
Z-3-[6-dimethylaminomethyl-3-(4-fluoro-benzylidene)-cyclohex-1-enyl]-phenol,
E-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
E-3-[3-(4-chloro-benzylidene)-6-dimethylaminomethyl-cyclohex-1-enyl]-phenol,
Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-Z-3-[4-dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-E-3-[3-chloro-4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-E-3-[4-dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-Z-3-[4-dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
(+)-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
(xe2x88x92)-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid methyl ester,
rac-trans-Z-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid methyl ester,
rac-cis-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid,
rac-cis-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid,
rac-trans-Z-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)benzoic acid,
rac-trans-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-triflluoromethyl-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-trifluoromethyl-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]benzoic acid methyl ester,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid E-[4-ethylidene-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethylamine
[4-isopropylidene-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethylamine,
E-[2-(3-methoxy-phenyl)-4-propylidene-cyclohex-2-enylmethyl]-dimethylamine,
E-[4-butylidene-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethylamine
and salts thereof, in particular hydrochloride salts.
The invention also provides a process for the preparation of substituted aminomethyl-phenyl-cyclohexane derivatives of the formula I or Ia 
in which R1, R1xe2x80x2, R2, R3, R4, R5 and X are as previously defined. According to the present invention cyclohexanones of the formula II or Iia 
in which R4, R5 and X are as defined above, R28 is as defined in the definition of R1, and R28xe2x80x2is as defined in the definition of R1xe2x80x2, are reacted in a Wittig reaction in an organic solvent in the presence of a base with alkyltriphenylphosphonium salts of the formula III 
wherein A denotes chloride or bromide and, independently of one another, R29 is as defined in the above definition of R2 and R30 is as defined in the above definition of R3.
Preferred organic solvents here are benzene, toluene or a chlorinated hydrocarbon, and potassium tert-butylate or sodium hydride are preferably used as the base. Furthermore, the reaction temperature, in particular during the Wittig reaction, is preferably kept between 50xc2x0 C. and 90xc2x0 C.
OH, SH and NH2 groups can undergo undesirable side reactions under the reaction conditions mentioned. It is therefore preferable to provide these with protective groups, or in the case of NH2 to replace it by NO2, and to remove the protective group or reduce the NO2 group after the Wittig reaction. The present invention therefore also provides a modification of the process described above in which in R28 and/or R28xe2x80x2 according to formula II or Ia and/or R29 and/or R30 according to formula III at least one OH group has been replaced by an OSi(Ph)2tert-but group, at least one SH group has been replaced by an S-p-methoxybenzyl group and/or at least one NH2 group has been replaced by an NO2 group and, after conclusion of the Wittig reaction, at least one OSi(Ph)2tert-but group is split off with tetrabutylammonium fluoride in tetrahydrofuran and/or at least one p-methoxybenzyl group is split off with a metal amine, preferably sodium amine, and/or at least one NO2 group is reduced to NH2.
Furthermore, carboxylic acid or thiocarboxylic acid groups are not stable under certain circumstances under the conditions of the Wittig reaction, so that it is preferable to react methyl esters thereof in the Wittig reaction and then to hydrolyse the process product from the Wittig reaction with KOH solution or NaOH solution in methanol at 40xc2x0 C.-60xc2x0 C. The invention therefore also provides a modification of the processes described above in which, after the Wittig reaction, a process product with at least one C(O)OCH3, OC(O)OCH3 and/or C(S)OCH3 group is hydrolyzed with KOH solution or NaOH solution in methanol at 40xc2x0 C.-60xc2x0 C.
The reactions proceed specifically and with high yields. Nevertheless, purification of the compounds obtained in the individual reaction sequences, in particular of the end product, is usually necessary. The purification is preferably carried out via crystallization or chromatographic methods, in particular column chromatography.
The compounds of formula I or Ia can be converted into their salts in a manner well-known to those of ordinary skill in the art with physiologically tolerated acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The salt formation is preferably carried out in a solvent, such as diisopropyl ether, acetic acid alkyl esters, acetone and/or 2-butanone. Trimethylchlorosilane in aqueous solution is particularly suitable for preparation of the hydrochlorides.
The cyclohexanones of formulae II and IIa are prepared by first reacting 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-8-one with immonium salts of the formula IV or with formaldehyde and an amine of the formula V. The Mannich bases obtained in this way are then reacted with an organometallic compound of the formula VI, in which Z denotes MgCl, MgBr, MgI or lithium. The reaction of the Mannich bases with a Grignard compound of the formula VI, in which Z denotes MgCl, MgBr or MgI, or with an organolithium compound of the formula VI, in which Z is Li, can be carried out in an aliphatic ether, for example diethyl ether and/or tetrahydrofuran, at temperatures of between xe2x88x9270xc2x0 C. and 60xc2x0 C. The reaction with a Grignard compound of the formula VI can be carried out with or without the addition of an entraining reagent. If an entraining reagent is employed, 1,2-dibromoethane is preferred. 
Products of the general formula VII are first obtained in this way. 
Compounds of the formula IIa are obtained by reacting products of the general formula VII with an acid, for example hydrochloric acid, formic acid or acetic acid, at room temperature. Subsequent hydrogenation of the products obtained in this way with catalytically activated hydrogen, platinum or palladium absorbed on a support material, such as active charcoal, serving as the catalyst, leads to compounds of the formula II where X is H. The hydrogenation is carried out in a solvent, such as ethyl acetate or a C1-C4-alkyl alcohol, under pressures of 0.1 to 10 bar and at temperatures of 20xc2x0 C. to 80xc2x0 C.
Compounds of the general formula II where X is OH are obtained by reacting products of the general formula VII with acids, for example hydrochloric acid, at temperatures of between 5xc2x0 C. and 10xc2x0 C.
Compounds of the general formula II where X is F, Cl, Br, I or CF3 are obtained by replacement of OH by F or Cl or Br or I or CF3 by processes well known to those ordinarily skilled in the art.
Compounds of the general formula II where X is OR7 are obtained by etherification of the OH group with a halide of the formula VIII;
R7Clxe2x80x83xe2x80x83VIII. 
Compounds of the general formula II where X is OC(O)R7 are obtained by esterification of the OH group with an acid chloride of the formula IX;
R7COClxe2x80x83xe2x80x83IX. 
Most of the substituted alkyltriphenylphosphonium salts used in the preparation process are commercially obtainable. However, in some exceptional cases these must be synthesized. 3-(Benzoic acid methyl ester)-methyltriphenylphosphonium bromide may be mentioned as an example of the synthesis of the substituted alkyltriphenylphosphonium salts: 
This is prepared as follows: 3-Toluic acid is converted with methanol in the presence of sulfuric acid into 3-toluic acid methyl ester, which reacts with N-bromosuccinimide to give 3-bromomethyl-benzoic acid methyl ester. Reaction of bromomethyl-benzoic acid methyl ester with triphenylphosphane finally leads to 3-(benzoic acid methyl ester)-methyltriphenylphosphonium bromide.
The substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention are toxicologically acceptable so that they are suitable as a pharmaceutical active compound in medicaments.
The invention therefore also provides medicaments which comprise, as the active compound, at least one substituted aminomethyl-phenyl-cyclohexane derivative of the general formula I or Ia 
in which R1, R1xe2x80x2, R2, R3, R4, R5 and X have one of the meanings mentioned in claim 1, in the form of its diastereomers or enantiomers and of its free base or of a salt formed with a physiologically tolerated acid, in particular a hydrochloride salt.
Medicaments which comprise as the active compound at least one substituted aminomethyl-phenyl-cyclohexane derivative chosen from the following group are particularly preferred here:
rac-cis-E-[-4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-trans-E-[4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-trans-Z-[4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-cis-Z-[4-benzylidene-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-naphthalene-1-carboxylic acid ethyl ester,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-2-methyl-cyclohex-2-enylidenemethyl]-naphthalene-1-carboxylic acid ethyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-2-fluoro-benzoic acid ethyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid,
E-{3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-phenyl}-methanol,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-[3-(2-dimethylaminomethyl-5-(3-hydroxymethyl-benzylidene)-cyclohexyl)-phenol,
rac-trans-E-3-(5-benzylidene-2-dimethylaminomethyl-cyclohexyl)-phenol,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid tert-butyl ester,
E-3-[6-dimethylaminomethyl-3-(3-hydroxymethyl-benzylidene)-cyclohex-1-enyl]-phenol,
rac-trans-Z-3-(5-benzylidene-2-dimethylaminomethyl-cyclohexyl)-phenol,
Z-3-[2-dimethylaminomethyl-5-(3-hydroxymethyl-benzylidene)-cyclohex-1-enyl]-phenol,
Z-{3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-phenyl}-methanol,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid tert-butyl ester,
rac-trans-E-[3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl)-phenyl)-methanol],
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid ethyl ester,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide rac-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide,
E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid ethyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-N,N-diethyl-benzamide,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-N,N-diethyl-benzamide,
E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid isobutyl ester,
Z-3-[6-dimethylaminomethyl-3-(3-hydroxymethyl-benzylidene)-cyclohex-1-enyl]-phenol,
Z-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
E-[4-(4-fluoro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
Z-[4-(4-fluoro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
E-3-[6-dimethylaminomethyl-3-(4-fluoro-benzylidene)-cyclohex-1-enyl]-phenol,
Z-3-[6-dimethylaminomethyl-3-(4-fluoro-benzylidene)-cyclohex-1-enyl]-phenol,
E-[4-(4-chloro-benzylidene)-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethyl-amine,
E-3-[3-(4-chloro-benzylidene)-6-dimethylaminomethyl-cyclohex-1-enyl]-phenol,
Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester,
E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-Z-3-[4-dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-E-3-[3-chloro-4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-E-3-[4-dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-cis-Z-3-[4-dimethylaminomethyl-3-hydroxy-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
(+)-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
(xe2x88x92)-trans-E-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid methyl ester,
rac-trans-Z-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid methyl ester,
rac-cis-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid,
rac-cis-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid,
rac-trans-Z-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)benzoic acid,
rac-trans-E-3-(4-dimethylaminomethyl-3-phenyl-cyclohexylidenemethyl)-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-triflluoromethyl-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-trifluoromethyl-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]benzoic acid methyl ester,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid methyl ester,
rac-trans-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-trans-Z-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid,
rac-cis-E-3-[4-dimethylaminomethyl-3-(3-fluoro-phenyl)-cyclohexylidenemethyl]-benzoic acid,
E-[4-ethylidene-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethylamine,
[4-isopropylidene-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethylamine,
E-[2-(3-methoxy-phenyl)-4-propylidene-cyclohex-2-enylmethyl]-dimethylamine, and
E-[4-butylidene-2-(3-methoxy-phenyl)-cyclohex-2-enylmethyl]-dimethylamine,
as a free base or in the form of a salt formed with a physiologically tolerated acid, in particular a hydrochloride salt.
The medicaments according to the invention comprise, in addition to at least one substituted aminomethyl-phenyl-cyclohexane derivative according to the invention, carrier materials, fillers, solvents, diluents, dyestuffs and/or binders and can be administered as liquid formulations such as injection solutions, drops or juices, or as semi-solid formulations, or as granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of auxiliary substances and the amounts thereof to be employed depends on whether the medicament is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, the mucous membranes and the eyes. Formulations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry formulations and sprays are suitable for parenteral, topical and inhalatory administration. Substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention in a depot in dissolved form or in a patch, optionally with the addition of agents which promote penetration through the skin, are suitable formulations for percutaneous administration. Formulation forms which can be used orally or percutaneously can release the substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention in a delayed manner. The amount of active compound to be administered to the patient varies according to the body weight of the patient, the mode of administration, the indication and the severity of the disease. 50 to 500 mg/kg of at least one substituted aminomethyl-phenyl-cyclohexane derivative according to the invention are usually administered.
The substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention are preferably employed for treatment of pain, so that the invention also provides the use of at least one substituted aminomethyl-phenyl-cyclohexane derivative of the general formula I or Ia 
in which R1, R1xe2x80x2, R2, R3, R4, R5 and X are as defined above, in the form of its diastereomers or enantiomers and of its free base or of a salt formed with a physiologically tolerated acid, in particular the hydrochloride salt, for the preparation of a medicament or a pharmaceutical composition for treatment of pain.
It has been found, surprisingly, that the substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention are very suitable for further indications, in particular for treatment of urinary incontinence, itching and/or diarrhoea, and also in other indications. The present invention therefore also provides the use of at least one substituted aminomethyl-phenyl-cyclohexane derivative of the general formula I or Ia 
in which R1, R1xe2x80x2, R2, R3, R4, R5 and X are as defined above, in the form of its diastereomers or enantiomers and of its free base or of a salt formed with a physiologically tolerated acid, in particular the hydrochloride salt, for the preparation of a medicament for treatment of inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, cardiovascular diseases, respiratory tract diseases, coughing, mental illnesses and/or epilepsy, and in particular urinary incontinence, itching and/or diarrhoea.
The invention is explained further by examples in the following, without limiting it thereto.